The iron chelating cardioprotective prodrug dexrazoxane does not affect the cell growth inhibitory effects of bleomycin

Wu, Xing; Patel, Daywin; Hasinoff, Brian B.

doi:10.1016/j.jinorgbio.2004.08.009

Cited by 9 publications

(3 citation statements)

References 34 publications

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“…It might be that a possible interference of the chelators with the antitumour activity of the cytostatic drugs was sufficiently counteracted by the antiproliferative action of the chelators. On the other hand, Wu et al (2004) previously showed that the antiproliferative effect of bleomycin was not compromised by dexrazoxane in a specially developed dexrazoxane-insensitive CHO cell line in which the confounding effect of the intrinsic antiproliferative effect of the chelator was eliminated.…”

Section: Discussionmentioning

confidence: 99%

Iron is not involved in oxidative stress‐mediated cytotoxicity of doxorubicin and bleomycin

Kaiserová

Hartog

Šimůnek

et al. 2006

British J Pharmacology

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Background and purpose: The anticancer drugs doxorubicin and bleomycin are well-known for their oxidative stressmediated side effects in heart and lung, respectively. It is frequently suggested that iron is involved in doxorubicin and bleomycin toxicity. We set out to elucidate whether iron chelation prevents the oxidative stress-mediated toxicity of doxorubicin and bleomycin and whether it affects their antiproliferative/proapoptotic effects. Experimental approach: Cell culture experiments were performed in A549 cells. Formation of hydroxyl radicals was measured in vitro by electron paramagnetic resonance (EPR). We investigated interactions between five iron chelators and the oxidative stress-inducing agents (doxorubicin, bleomycin and H 2 O 2 ) by quantifying oxidative stress and cellular damage as TBARS formation, glutathione (GSH) consumption and lactic dehydrogenase (LDH) leakage. The antitumour/proapoptotic effects of doxorubicin and bleomycin were assessed by cell proliferation and caspase-3 activity assay.Key results: All the tested chelators, except for monohydroxyethylrutoside (monoHER), prevented hydroxyl radical formation induced by H 2 O 2 /Fe 2 þ in EPR studies. However, only salicylaldehyde isonicotinoyl hydrazone and deferoxamine protected intact A549 cells against H 2 O 2 /Fe 2 þ . Conversely, the chelators that decreased doxorubicin and bleomycin-induced oxidative stress and cellular damage (dexrazoxane, monoHER) were not able to protect against H 2 O 2 /Fe 2 þ . Conclusions and implications:We have shown that the ability to chelate iron as such is not the sole determinant of a compound protecting against doxorubicin or bleomycin-induced cytotoxicity. Our data challenge the putative role of iron and hydroxyl radicals in the oxidative stress-mediated cytotoxicity of doxorubicin and bleomycin and have implications for the development of new compounds to protects against this toxicity.

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Section: Discussionmentioning

confidence: 99%

Iron is not involved in oxidative stress‐mediated cytotoxicity of doxorubicin and bleomycin

Kaiserová

Hartog

Šimůnek

et al. 2006

British J Pharmacology

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“…However, use of the drug is limited by pulmonary toxicity. In a recent study, dexrazoxane was observed to reduce bleomycin toxicity without adversely altering the antitumour action of the drug (Wu et al 2004).…”

Section: Drugs That Require Iron For An Activitymentioning

confidence: 99%

Therapeutic potential of iron chelators in diseases associated with iron mismanagement

Weinberg

2006

Journal of Pharmacy and Pharmacology

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A considerable array of diseases are now recognized to be associated with misplacement of iron. Excessive deposits of the metal in sensitive tissue sites can result in formation of destructive hydroxyl radicals as well as in stimulation of growth of neoplastic and microbial cell invaders. To counteract potential iron damage, hosts employ the iron chelators, transferrin and lactoferrin. These proteins have been recently developed into pharmaceutical products. Additionally, a variety of low molecular mass iron chelators are being used/tested to treat whole body iron loading, and specific diseases for which the metal is a known or suspected risk factor.

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“…In fact, bleomycin is commonly used to induce experimental pulmonary fibrosis in rodents as a model of a fibro-inflammatory interstitial lung disease (Snider et al 1978;Adamson and Bowden 1974). The biological effect of bleomycin is dependent on its coordination of iron, with chelating agents such as dexrazoxane, reducing its toxic effects (Wu et al 2004).…”

Section: Introductionmentioning

confidence: 99%

Deficiency in the divalent metal transporter 1 increases bleomycin-induced lung injury

et al. 2010

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Exposure to bleomycin can result in an inflammatory lung injury. The biological effect of this anti-neoplastic agent is dependent on its coordination of iron with subsequent oxidant generation. In lung cells, divalent metal transporter 1 (DMT1) can participate in metal transport resulting in control of an oxidative stress and tissue damage. We tested the postulate that metal import by DMT1 would participate in preventing lung injury after exposure to bleomycin. Microcytic anemia (mk/mk) mice defective in DMT1 and wild-type mice were exposed to either bleomycin or saline via intratracheal instillation and the resultant lung injury was compared. Twenty-four h after instillation, the number of neutrophils and protein concentrations after bleomycin exposure were significantly elevated in the mk/mk mice relative to the wild-type mice. Similarly, levels of a pro-inflammatory mediator were significantly increased in the mk/mk mice relative to wild-type mice following bleomycin instillation. Relative to wild-type mice, mk/mk mice demonstrated lower non-heme iron concentrations in the lung, liver, spleen, and splenic, peritoneal, and liver macrophages. In contrast, levels of this metal were elevated in alveolar macrophages from mk/mk mice. We conclude that DMT1 participates in the inflammatory lung injury after bleomycin with mk/mk mice having increased inflammation and damage following exposure. This finding supports the hypothesis that DMT1 takes part in iron detoxification and homeostasis in the lung.

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The iron chelating cardioprotective prodrug dexrazoxane does not affect the cell growth inhibitory effects of bleomycin

Cited by 9 publications

References 34 publications

Iron is not involved in oxidative stress‐mediated cytotoxicity of doxorubicin and bleomycin

Iron is not involved in oxidative stress‐mediated cytotoxicity of doxorubicin and bleomycin

Therapeutic potential of iron chelators in diseases associated with iron mismanagement

Deficiency in the divalent metal transporter 1 increases bleomycin-induced lung injury

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